Pharmaceutical compositions

ABSTRACT

The physiologic availability of a muscle relaxant, 1-(5-(pnitrophenyl)furfurylideneamino)hydantoin, in the form of its sodium salt when administered orally to man in capsule form containing a formulation comprising it, lactose, starch, talc and magnesium stearate is increased at least twofold.

United States Patent Conklin et al. v

1151 73,689,654 1 51 Sept. 5, 1972 [54] PHARMACEUTICAL COMPOSITIONS [72] Inventors: John D. Conklin; Edward L.

DOrazio, both of Norwich, NY.

[7 3] Assignee: Morton-Norwich Products, Inc.,

[22] Filed: Sept. 14, 1970 [21] Appl. No.: 72,196

[52] US. Cl ..424/273 [51] Int. Cl. ..A6lk 27/00 [58] Field of Search ..424/285, 273

References Cited UNITED STATES PATENTS 3,415,821 12/1968 Davisetal 424/273 Primary Examiner-Stanley J Friedman Attorney-Bradford S. Allen [57] ABSTRACT 1 Claim, No Drawings PHARMACEUTICAL COMPOSITIONS Sodium l-[-( p-nitrophenyl)furfurylideamino] hydantoin Equivalents This invention relates to pharmaceutical composimeg/mu tions. More particularly it 1s related to a pharmaceutical composition in capsule form containing a drug formulation whereby physiologic availability of the drug is 5 Table II increased. Still more particularly it is concerned with the provision of a muscle relaxant, I-[S-(p-nitrophen- Unnarypmg i f Oral yl)furfurylideneamino]hydantoin in the form of its Admlmstranon 9 Sodmn? sodium salt, composed in capsule form in a formulation mtrophenynfurfurylldeneammo]hydamom gtcgsrizgng of lactose, starch, talc and magnesium (Pure Drug Formulation) The compound l-[5-(p-nitrophenyl)furfury- Urinary Drug Rfcovery lideneaminolhydantoin and its utility as a muscle relax- M8 Mean for Two Doses ant are dCSCI'lbBd in U.S. Pat. N0. 3,415,821. A180 Pure Drug Formulation (25-75 mg)/Volunteer pointed out in that patent is the formulation of that subject 25 75 75 Pm fmmulam" compound in various pharmaceutical compositions including capsules. AP 10.2 5.0 19.8 14.2 7.6 17.0 It has been unex ectedl discovered that when l-[5- JB P Y JU 5.8 3.5 19.1 10.2 4.6 14.6 (p-mtrophenyl)furfuryhdeneammo]hydanto1n 1n the .111 3.8 9.9 15.9 16.9 6.8 16.4 form of its sodium salt is admixed with lactose, starch, g; 3'3 {8'2 8'3 2'3 18-? talc and magnesium stearate and that composition CD 9.2 10.6 22.4 13.4 9.9 17.9 placed in a gelatin capsule for oral administration to g; g-g g-Z 3: man at least a twofold increase in physiologic availabili- DH 1 ty of drug 1s achieved. Exemplary of such a formulat1on JC 50 3.4 6-3 7.9 is the following. FA 16.5 4.9 10.2 21.2 10.7 15.7

ingredient Amount per Capsule Mean 7.9 6.5 15.0 l2.3 1s.1) 3.7 2.8 4.5 4.4 Sodiuml-{S-(pnitrophenyl)furfurylideneaminognhydantoin 25-100 mg. Lac 126-232 Calculated on the basis of sodium l-[5-( p-nitrophenyUfurfury- Starch 20-35 m lideneaminolhydantoin dosed. Talc l0-20 mg. Magnesium Stearate 5-10 mg.

The capsules employed in the foregoing tests contained the following in addition to sodium l-[5-(pnitrophenyl)furfurylideneamino]hydantoin sodium: In preparmg such formulation conventional pharmaceutical compounding techniques are employed, the

25m .Ca sule 75m .Ca sule drug being 1nt1mately dispersed in the exclprents by g p g p grinding, stirring or blending.

L t 170 207 When sodium 1-[5-(p-n1trophenyl)furfury- :33, 25 20 lidenanino1hydantoin administered to man in a single Talc 10 mg. 10 mg. Magnesium stearate 5 mg. 5 mg.

dose of 25 mg. or 75 mg. and is similarlyadministered without excipients, the following results are obtained on analysis of the urine and blood of the recipient using a method for detecting dantrolene described in Arch. The surpnsmg enhancement of the Physlologlc Int pharmacodyn 174.333, 1968; ava1lab1l1ty of dantrolene sodmm as represented 1n the foregomg tables 1s not now suscept1ble of explananon TABLEI not is there presently at hand any soundly based theory to account for it. Human Blood Drug Concentrations Followmg Oral What is claimed is:

Admmlstraton 9 '9 1. A muscle relaxant pharmaceutical composition in mtrophenybfurfuryhdeneammo]by amom capsule dosage form selected from the group consisting (Pure Drug vs. Formulation) of:

Blood Drug Conc. mcg/ml* a. Sodium l-[S-(pnitrophenyl)furfurylideneaminognhydantoin 25 mg. Drug- 1.5 3.0 4.5 6.0 7.5 9.0 [0.5 12.0 Lactose 170 mg. Dose hr hr hr hr hr hr hr hr Starch 25 mg. Talc 10 mg. Magnesium stearate 5 mg. Pure Drug 0.01 0.04:0.09 0.10 0.09 0.09 0.09 0.07 25 mg 20.05 d Formulation 0.13 0.28 0.30 0.28 0.25 0.23 0.21 0.16 25mg 10.0910.1&0.11 10.131014 101310.13 10.11 Pure Drug 0.09 0.220.36 0.37 0.33 0.35 0.33 0.27 b Sodiu m l-[5-( p- 75 mg 019 i019 i010 iols i018 1017 nitrophenyl)furfurylideneaminognhydantoin 75 mg. Formulation 0.48 0.80 0.90 Lactose 207 m 0.85 0.78 0.75 0.70 0.58 starch 20 m mg 10.37 104E004 10.42 10.38 10.32 10.33 10.28 Talc 10 g- Magnesium stearate 5 mg.

@253? UNITED STATES PATENT OFFICE Patent No. 3, 689, 654 Dated September 5, 1972 mie fls) John D. Conklin; Edward L. D'Orazio It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 30: "nitrophenyl)furfurylideneaminognhydantoin" should be --nitrophenyl)furfurylideneaminohydantoin-- v Column 1, line 41: "lidenanino" should be --lidenamino-- Column 1, line 41: after "hydantoin" insert --in the aforesaid capsule formulation is-- t v Column 1, line 60: Opposite "Pure Drug and under "3. 0" 0. 0" should be 0. 04- Column 1, line 64: Opposite "Formulation" and under "6. 0" should be entered O. 85 Opposite'Formulation and under "'7. 5" should be entered --O. '78- I Column 1, line 65: Strike "0. 85" and "O. 78"; move "0. 75", "0'. '70" and "O. 58" up one line. Column 2, line 1: Insert an asterisk before "Sodium". Column 2, line 56: "nitrophenyl)furfurylideneaminognhydantoin" should be -nitrophenyl)furfurylideneaminohydantoin- Column 2, line 63: "nitrophenyl)furfurylideneaminognhydantoin" should be nitrophenyl)furfurylideneaminohydantoin- I I Signed and sealed this 13th day of February 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCI-IALK Attesting Officer Commissioner of Patents 

